21-44289793-C-T

Variant names:

• chr21-44289793-C-T
• rs138066507
• NM_000383.4:c.789C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_000383.4(AIRE):​c.789C>T​(p.Gly263Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000853 in 1,612,616 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G263G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00096 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00084 (5 hom.)
• Consequence: AIRE NM_000383.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.708
• Publications: 1 publications found

Genes affected

AIRE (HGNC:360): (autoimmune regulator) This gene encodes a transcriptional regulator that forms nuclear bodies and interacts with the transcriptional coactivator CREB binding protein. The encoded protein plays an important role in immunity by regulating the expression of autoantigens and negative selection of autoreactive T-cells in the thymus. Mutations in this gene cause the rare autosomal-recessive systemic autoimmune disease termed autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED). [provided by RefSeq, Jun 2012]

AIRE Gene-Disease associations (from GenCC):

• autoimmune polyendocrine syndrome type 1

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Genomics England PanelApp
• familial isolated hypoparathyroidism due to impaired PTH secretion

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 21-44289793-C-T is Benign according to our data. Variant chr21-44289793-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 128335.
• BP7: Synonymous conserved (PhyloP=-0.708 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000383.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIRE	NM_000383.4	MANE Select	c.789C>T	p.Gly263Gly	synonymous	Exon 6 of 14	NP_000374.1	O43918-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIRE	ENST00000291582.6	TSL:1 MANE Select	c.789C>T	p.Gly263Gly	synonymous	Exon 6 of 14	ENSP00000291582.5	O43918-1
	AIRE	ENST00000966178.1		c.789C>T	p.Gly263Gly	synonymous	Exon 6 of 14	ENSP00000636237.1
	AIRE	ENST00000527919.5	TSL:2	n.1522C>T		non_coding_transcript_exon	Exon 6 of 14

Frequencies

GnomAD3 genomes AF: 0.000959 AC: 146 AN: 152204 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00149 AC: 369 AN: 247366 AF XY: 0.00156

Gnomad AFR exome AF: 0.0000652

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.0288

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000459

Gnomad OTH exome AF: 0.00364

GnomAD4 exome AF: 0.000842 AC: 1229 AN: 1460294 Hom.: 5 Cov.: 34 AF XY: 0.000909 AC XY: 660 AN XY: 726438

African (AFR) AF: 0.0000896 AC: 3 AN: 33472

American (AMR) AF: 0.000268 AC: 12 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0288 AC: 753 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52068

Middle Eastern (MID) AF: 0.00106 AC: 6 AN: 5674

European-Non Finnish (NFE) AF: 0.000262 AC: 291 AN: 1111926

Other (OTH) AF: 0.00270 AC: 163 AN: 60354

GnomAD4 genome AF: 0.000958 AC: 146 AN: 152322 Hom.: 1 Cov.: 33 AF XY: 0.000940 AC XY: 70 AN XY: 74486

African (AFR) AF: 0.000144 AC: 6 AN: 41588

American (AMR) AF: 0.000653 AC: 10 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 108 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68002

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00225 Hom.: 1

Bravo AF: 0.00109

EpiCase AF: 0.000872

EpiControl AF: 0.00101

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	Polyglandular autoimmune syndrome, type 1 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.4
DANN	Benign	0.71
PhyloP100		-0.71
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs138066507; hg19: chr21-45709676;